electrophylic molecules that are attacked by nucleophilic sites on DNA, resulting in the covalent attachment of an alkyl group to the nucleophilic site; also drugs that covalently couple alkyl groups to nucleophilic sites on DNA

affect cell function in all phases and thus are CELL CYCLE NON-SPECIFIC

Alkylating Agents

Nitrogen mustards, nitrosoureas, alkyl sulfonates, other

Are all CCNS drugs. Form reactive molecular species by alkylating DNA bases (guanine usually)

located on most types of smooth muscle, cardiac muscle, some presynaptic terminals, and lipocytes.

Anaphylaxis

A severe life threatening hypersensitivity reaction to a previously encountered antigen that results in vasodilation and subsequent hypotension.

IgE mediated via degranulated mast cells

Anaphylaxis

Allergic reaction resulting in the narrowing of airways and a significant decrease in blood pressure. Epinephrine is the drug of choice for immediate treatment.

Anaphylaxis

life threatening hypersensitivity reaction caused by systemic mast cell degranulation from exposure to an allergen in a previously sensitized individual

Antimetabolite

A drug that is very similar to natural chemicals in a normal biochemical reaction in cells but different enough to interfere with the normal division and functions of cells.

Used commonly as anti-neoplastics. Most effective against rapidly growing tumors

Acts primarily on S-phase of cell cycle

Antimetabolite

A drug that is very similar to natural chemicals in a normal biochemical reaction in cells but different enough to interfere with the normal division and functions of cells. Used commonly as anti-neoplastics. Most effective against rapidly growing tumors

Antimetabolite

Act primarily in the S phase of the cell cycle, causing cytotoxic effects on neoplastic cells and immunosuppressant actions. Used in cancer chemotherapy.

antimetabolite

a chemical that inhibits the use of a metabolite (a chemical normally used in metabolism); often similar in structure to the metabolite they interfere with; often have toxic effects on cells- halting cell growth and division-->

USED AS CHEMOTHERAPY FOR CANCER

Antimetabolites

Antagonists of: folic acid, purines, pyrimidines.

Act primarily during S phase of the cell cycle. Also have immunosuppression actions

Antimetabolites

CCS

Autoreceptor

receptor which responds to neurotransmitter which the cell itself released

regulates synthesis and release of neurotransmitter

Autoreceptor

receptor which responds to neurotransmitter which the cell itself released regulate synthesis and release of nuerotransmitter

Autoreceptor

Presynaptic receptors that bind the primary transmitter substance and thereby regulate its release

autoreceptor

receptors that regulate NT release; some NTs may also bind to a third class of receptors on the PRE-synaptic membrane

Bioavailability(F)

Fraction of drug that's available in the blood stream following administration via a given route (po, pr, pv, transderm) as compared to IV administration (which is 100%)

F = AUCpo ÷ AUCIV

Bioavailability(F)

Fraction of drug that's available in the blood stream following administration via a given route (po, pr, pv, transderm) as compared to IV administration (which is 100%)

Bioavailability

The fraction (or percentage) of the administered dose of drug that reaches the systemic circulation

Group of endogenous fatty acid autacoids that are produced from arachidonic acid, including leukotrienes, prostacyclin, prostaglandins, and thromboxane.

catecholamine

biochemical substances, epinephrine, norepinephrine, and dopamine, that have a marked effect on the nervous system, cardiovascular system, metabolic rate, temperature, and smooth muscle.

Metabolized by COMT

catecholamine

biochemical substances, epinephrine, norepinephrine, and dopamine, that have a marked effect on the nervous system, cardiovascular system, metabolic rate, temperature, and smooth muscle.

Catecholamine

A dihydroxyphenylethylamine derivative (eg, norepinephrine, epinephrine), a relatively polar molecule that is readily metabolized by catechol-O-methyltransferase

catecholamine

class of NT derived from oxidation of tyrosine; includes dopamine, norepinephrine, and epinephrine; most synthesis occurs at the synaptic nerve ending; modulate many vita sympathetic/parasympathetic functions; many drugs target their synthesis, release, storage, uptake, and post-synaptic receptors

Chelator

organic compounds that form 2 or more bonds with a central metal ion

(Ex: Deferoxamine & EDTA are used to chelate iron in iron toxicity)

Chelator

Function as chemical antagonists, used as antidotes int he treatment of heavy metal poisoning

A drug that is an enzyme inducer causes the liver to over produce enzymes responsible for the metabolism of that or other drugs (substrates)

Enzyme induction

Stimulation of drug-metabolizing capacity; usually manifested in the liver by increased synthesis of smooth ER

enzyme induction

increased expression of an enzyme through increased transcription/translation or decreased degradation

Enzyme Inhibition

Occurs when the substrate is unable to bind to the active site of an enzyme. Inhibition of CYP450 by one drug can lead to the accumulation of other drugs that are metabolized by that enzyme

Enzyme Inhibition

occurs when a molecule binds to an enzyme and decreases its activity

enzyme inhibition

drug or metabolite binds to an enzyme (active site or other) and causes a change in which the enzyme can no longer metabolize drugs; can happen through competitive, mixed, or irreversible inhibition

FDA medication guide

Paper handouts that are mandated by law to be provided with specific prescription drugs that outlines indications, administration, adverse effects

FDA medication guide

Paper handouts that are mandated by law to be provided with specific prescription drugs that outlines indications, administration, adverse effects

Ex: PPIs, SSRIs, NSAIDs, amphetamines, anticonvulsants

FDA medication guide

required by FDA to be issued with certain drugs when:

1- certain info necessary to prevent adverse side effects

2- patient decision making should be informed by knowledge of a known serious side effect of the drug, or patient adherence is essential to its effectiveness

First Order Kinetics

Zero order kinetics

capacity limited elimination- clearence will vary depending on the concentration of the drug that is achieved (the drug elimination pathway is saturated; clinically seen when small changes in dosage results in large increases of drug plasma concentration); Ex: aspirin, ethanol, phenytoin

First-order kinetics

the rate of drug elimination is proportional to the plasma drug concentration and follows an exponential decay function (most drugs).

first order kinetics

the amount of drug that is metabolized or excreted in a given unit of time is directly proportional to its concentration in systemic circulation

phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation; the fraction lost during the process of absorption, generally related to liver and gut wall

study of how genetic differences in multiple genes influence the variability in patients' response to drugs

Ex: Different genes cause differences in metabolizing drugs. Also genes can affect how you respond to drug therapy or what adverse reactions you experience

Pharmacogenomics

Genetic variations in drug metabolism

pharmacogenomics

correlates gene expression and SNPs with drug efficacy and toxicity

Pharmacology

study of drugs and their interactions with living systems

~studies the physical and chemical properties of drugs as well as their biochemical and physiologic effects

Pharmacology

The body of knowledge concerned with the action of chemicals on biologic systems

pharmacology

study of drug action and effect on cells, tissues, organs

potency (EC50) vs. efficacy (Emax)

potency refers to the concentration (EC50) of a drug required to produce 50% of that drug’s maximal effect, on the dose axis;

Efficacy: the maximal effect that can be achieved with a particular drug, regardless of dose

potency (EC50) vs. efficacy (Emax)

potency refers to the concentration (EC50) of a drug required to produce 50% of that drug’s maximal effect, on the dose axis; Efficacy refers to the response (therapeutic effect) to a drug, on the response axis

Prodrug

A drug that is administered in its inactive form and requires the body to metabolize it into an active form

Ex: Levodopa, carisoprodol, valacyclovir, heroin

Prodrug

Inactive as administered and must be metabolized in the body to become active

prodrug

an inactive compound that is metabolized by the body into its active, therapeutic form

Toxin vs. poison

Toxin is synthesized by plants, animals, microorganisms, or insects. Poison is synthetic or inorganic (such as Mercury)

Protein Binding

Once in circulation, some percentage of the drug will be attracted to the protein in circulation and attach to form a reversible bond.

This drug that attaches is a “bound”drug – it is bound to protein

This drug is not available to exact a therapeutic effect

Protein Binding

Once in circulation, some percentage of the drug will be attracted to the protein in circulation and attach to form a reversible bond.

This drug that attaches is a “bound”drug – it is bound to protein

This process is called Protein Binding

Commonly albumin

All drugs have different degrees of protein binding

Protein binding

Drugs produce their effects by binding to protein receptors in target tissues, a process that activates a cascade of events known as signal transduction.

Receptor

a cellular macromolecule to which medication binds in order to initiate its effects

Receptor

The molecular components of the body with which drugs interact to bring about their effects

receptor

target molecule of a drug

steady-state drug concentration

concentration of drug in a body fluid (usually plasma) at the time a "steady state" has been achieved - i.e. rate of drug administration and drug elimination are equal

Steady-state drug concentration

In pharmacokinetics, the condition in which the average total amount of drug in the body does not change over multiple dosing cycles (ie, the condition in which the rate of drug elimination equals the rate of administration)

steady-state drug concentration

(fraction absorbed X maintenance dose)/(dosing interval X clearance)

sympathomimetic vs. sympatholytic/sympathoplegic drug

sympathomimetic mimic the effects of trasmitter substances of the SNS like catcholamines, epinephrine, norepinephrine, and dopamine

sympatholytic/sympathoplegic is a medication which inhibits the postganglionic functions of the SNS

sympathomimetic vs. sympatholytic/sympathoplegic drug

sympathomimetic mimic the effects of trasmitter substances of the SNS like catcholamines, epinephrine, norepinephrine, and dopamine (e.g. drugs to treat cardiac arrest and low blood pressure); sympatholytic/sympathoplegic is a medication which inhibits the postganglionic functions of the SNS (e.g. antihypertensives, used to treat anxiety)

Tachyphylaxis

Rapid decrease in responsiveness to drug (receptor desensitization)

Tachyphylaxis

Rapid loss of responsiveness to a stimulus (eg, a drug)

tachyphylaxis

rapidly decreasing response to a drug or physiologically active agent after administration of a few doses

Teratogen

An agent that can cause birth defects.

Ex: Thalidomide, Warfarin, Alcohol

Teratogen

An effect on the in utero development of an organism resulting in abnormal structure or function, not generally heritable.

teratogen

drug or other substance causing birth defects

Therapeutic index

A measure of a drug's safety.

consists of the LD50/ED50.

a therapeutic index of 3 tells us that 50 percent lethal dosage is only 3 times the 50 percent effective dosage

i.e.: You want your therapeutic index to be high because that means your effective dose and your lethal dose are far apart

Therapeutic index

The ratio of the TD50 (or LD50) to the ED50, determined from quantal dose-response curves. Represents an estimate of the safety of a drug.

therapeutic index

LD50/ED50

measure of toxicity, median lethal dose over median effective dose

Pharmacokinetic vs pharmacodynamic tolerance

kinetic - increased metabolism of the drug (barbiturates)

dynamic - receptor changes to decrease effect of drug

Toxicology

the study of the adverse effects of chemical agents on biological systems (Poisons)

Toxicology

The area of pharmacology concerned with the undesirable effects of chemicals on biologic systems

toxicology

study of poisons and their effect on cells, tissues and organs

Xenobiotic

any substance, harmful or not that is foreign to the body

Xenobiotic

Foreign chemical compunds

xenobiotic

foreign substance not naturally found in the body; include most drugs used to modulate bodily functions for therapeutic ends

- Linkage Disequilibrium: May be used as a marker if co-inherited with a disease-associated gene because of proximity

Single Nucleotide Polymorphism (SNP)

Variants at one nucleotide position, almost always biallelic (only two choices exist at a given site within the population, like A or T)

Single nucleotide polymorphisms (SNPs)

a DNA sequence variation occurring commonly within a population (e.g. 1%) in which a Single Nucleotide — A, T, C or G — in the genome (or other shared sequence) differs between members of a biological species or paired chromosomes

Single nucleotide polymorphisms (SNPs)

naturally occurring variations in DNA sequence characterized by insertions or deletions of a single nucleotide

Copy Number Variations (CNV)

Genetic variation of different numbers of large contiguous stretches of DNA from 1000 bp to millions of bp.

- can be simple & biallelic or complex with multiple alleles

- 50% found in gene coding sequences, and hence, could influence phenotypic diversity

Copy Number Variations (CNV)

Genetic variation of different numbers of large contiguous stretches of DNA

Copy number variations (CNVs)

a form of structural variation—are alterations of the DNA of a genome that results in the cell having an abnormal or, for certain genes, a normal variation in the number of copies of one or more sections of the DNA.

CNVs correspond to relatively large regions of the genome that have been deleted (fewer than the normal number) or duplicated (more than the normal number) on certain chromosomes

Copy Number Variations (CNVs)

a form of genetic variation between persons in which large, contiguous stretches of DNA that may be deleted, duplicated, or rearranged in subsets of humans. About 50% of known CNVs involve coding sequences, contributing to phenotypic diversity.

Nucleosome

DNA segments 147 bp long that are wrapped around a central core of highly conserved low MW proteins called histones

nucleosome

basic unit of DNA packaging in eukaryotes, consisting of a segment of DNA wound in sequence around eighthistone protein cores.

This structure is often compared to thread wrapped around a spool.

Histone Marks

"Chromatin writer" complexes carry out more than 70 different histone modifications. These covalent alterations include methylation, acteylation, or phosphorylation of specific AA residues on histones. "Chromatin Erasers" eliminate the marks and "Chromatin Readers" bind the marks and regulate gene expression.

Examples:

- Actively transcribed genes in euchromatin have marks that make DNA accessible to RNA polymerase

Histone modifications including methylation, acetylation, or phosphorylation of specific AA residues on histones.

Ex: actively transcribed genes in euchromatin have marks that make DNA accessible to RNA polymerase. Inactive genes have marks that enable DNA compactions into heterochromatin

Heterochromatin

Nuclear chromatin that is cytochemically dense and transcriptionally inactive

heterochromatin

a tightly packed form of DNA, which comes in different varieties. These varieties lie on a continuum between the two extremes of constitutive and facultative heterochromatin. Both play a role in the expression of genes

lightly packed form of chromatin (DNA, RNA and protein) that is rich in gene concentration, and is often (but not always) under active transcription. This comprises the most active portion of the genome within the cell nucleus. 92% of the human genome is this type of chromatin

micro-RNA (miRNA)

Small noncoding RNA <200 nucleotides (average ~22) that function primarily to modulate the translation of target mRNA into their corresponding proteins.

- Post-Tx silencing of gene expression by miRNA is a fundamental and well-conserved mechanism of gene regulation in all eukaryotes.

Shuttle internalized material to the appropriate intracellular sites or direct newly synthesized materials to the cell surface or targeted organelle

endosome

membrane-bounded compartment inside eukaryotic cells. It is a compartment of the endocytic membrane transport pathway from the plasma membrane to the lysosome.

Lysosome

Involved in cellular catabolism, they are intracellular organelles that contain degradative enzymes that permit the digestion of a wide range of macromolecules (proteins, polysaccharides, lipids, and nucleic acids).

a membrane-boundcell organellefound in animal cells (they are absent in red blood cells). They are structurally and chemically spherical vesicles containinghydroliticenzymes, which are capable of breaking down virtually all kinds of biomolecules, including proteins, nucleic acids,carbohydrates, lipids, and cellular debris.

protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in thenucleus and the cytoplasm

The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, achemical reaction that breaks peptide bonds.

Peroxisome

Specialize in very long-chain fatty acid metabolism, generating hydrogen peroxide in the process

peroxisome

organelles found in virtually all eukaryotic cells. They are involved in the catabolism of very long chain fatty acids, branched chain fatty acids, D-amino acids, and polyamines, and biosynthesis of plasmalogens, i.e. ether phospholipids critical for the normal function of mammalian brains and lungs

large (>100 proteins) macromolecular complexes that can be localized at hemi-desmosomes, and include proteins that can generate intracellular signals when cells are subjected to increased shear stress, such as endothelium in the blood stream (this all falls under 'Anchoring Junctions / Desmosomes')

Focal adhesion complex

large macromolecular complexes that can be localized at hemi-desmosomes and include proteins that can generate intracellular signals when cells are subjected to increased shear stress

focal adhesion complex

large macromolecular assemblies through which both mechanical force and regulatory signals are transmitted. They can be considered as sub-cellular macromolecules that mediate the regulatory effects (e.g. cell anchorage) of ECM adhesion on cell behavior.

They serve as the mechanical linkages to the ECM, and as a biochemical signaling hub to concentrate and direct numerous signaling proteins at sites of integrin binding and clustering

Unfolded Protein Response (ER Stress Response)

Results from excess accumulation of misfolded proteins - exceeding the capacity of the ER to edit and degrade them- which then triggers cell death through apoptosis

Autophagy

How senescent organelles and large, denatured protein complexes are shuttled into lysosomes. Obsolete organelles are corralled by a double membrane derived from ER, which expands to encircle a collection of structures and forms an autophagosome. The autophagosome fuses with lysosomes and the contents are catabolized. This helps turnover aged/defunct structures, as well as preserve cell viability during nutrient depletion.

Autophagy

How senescent organelles and large, denatured protein complexes are shuttled into lysosomes. To turnover aged/defunct structures

autophagy

basic catabolic mechanism that involvescell degradation of unnecessary or dysfunctional cellular components through the actions of lysosomes

Cellular Receptors associated with Kinase Activity

Often downstream phosphorylation transduces these signals, which allows alterations in receptor geometry to elicit intrinsic receptor protein kinase activity or promote the enzymatic activity of recruited intracellular kinases = adding phosphate. For every kinase, there is a phosphatase as well that inhibits the signal transduction. Types include Tyr Kinase, Ser/Thr kinase, and lipid kinase

G-Protein Coupled Receptors

Polypeptides that characteristically traverse the plasma membrane 7 times, that after a ligand binds, the receptor associates with a intracellular GTP-binding protein to exchange GDP For GTP, that then downstream also creates cAMP and IP3 (IP3 releases Ca from ER)

G-protein coupled receptors

traverse the plasma membrane 7 times. After a ligand binds, the receptor associated with an intracellular GTP-binding protein to exchange GDP for GTP, creating cAMP and IP3, causing release of calcium from the ER

Interstitial Matrix

The extracellular matrix (ECM) in the spaces between cells in connective tissue, and between the parenchymal epithelium and the underlying supportive vascular & smooth muscle structures. It is synthesized by mesenchymal cells (fibroblasts), to form a 3D gel and its major constituents are fibrillar & nonfibrillar collagen, fibronectin, elastin, proteoglycan, hyaluronate, and others.

Interstitial matrix

ECM, 3D gel in the spaces between cells in connective tissue and between the parenchymal epithelium and the underlying supportive vascular and smooth muscle structures.

thin sheet of fibers that underlies the epithelium which lines the cavities and surfaces of organs including skin, or the endothelium which lines the interior surface of blood vessels

Integrins

a kind of adhesion receptor that are called Cell Adhesion Molecules (CAMs). Integrins are a family of transmembrane heterodimeric glycoproteins (a and B subunits) that allow cells to attach to ECM constituents such as laminin and fibronectin, linking the intracellular cytoskeleton to the outside world via RGD.

family of transmembrane heterodimeric glycoproteins that allow cells to attach to ECM constituents such a laminin and fibronectin, linking the intracellular cytoskeleton to the outside world

integrins

transmembrane receptors that are the bridges for cell-cell and cell-extracellular matrix (ECM) interactions

Embryonic Stem Cells (ES Cells)

The most undifferentiated stem cells, present in the inner cell mass of the blastocyst, have limitless cell renewal capacity, and can give rise to every cell in the body (TOTIPOTENT). They can be induced to form specialized cells of all 3 germ cell layers, including neurons, cardiac muscle, liver cells, and pancreatic islet cells.

Tissue Stem Cells (Adult Stem Cells)

Found in intimate association with the differentiated cels of a given tissue, usually protected within specialized tissue microenvironments called 'Stem Cell Niches'. Adult stem cellls have limited repertoire of differentiation, usually only their cell type, even if the turnover rate is high (GI, Skin) or low (heart, brain). These express histocompatibility (HLA) molcules that provoke immunogenic responses.

Tissue Stem Cells (adult stem cells)

Have limited repertoire of differentiation, usually only produce cells that are normal constituents of that tissue

Induced Pluripotent Stem cells (iPS Cells)

Cells made when genes whose products can reprogram somatic cells to achieve the "stem-ness" of ES cells are introduced to a fully differentiated cells, like a fibroblast. Usually derived from the patient so they can be engrafted without rejection. Final product is a cell derived from the patient that have genes to be totipotent like ES cells.

Stem Cell Niche

A protected, specialized tissue microenvironments where adult stem cells are found in intimate association with the differentiated cels of a given tissue, in organs like the brain, hair follicle for skin and limbus for cornea, where they are quiescent until needed for differentiation.

Stem cell niche

specialized tissue microenvironment where adult stem cells are found

stem cell niche

a microenvironment where stem cells are found, which interacts with stem cells to regulate cell fate

Verapamil is a P-Glycoprotein __________.

Inhibitor

Substrate

Cyclosporin is a P-Glycoprotein __________.

Inhibitor

Susbtrate

Cyclosporin is a P-Glycoprotein __________.

Substrate

Inhibitor

Ritonavir is a P-Glycoprotein __________.

Inhbitor

Midazolam is a P-Glycoprotein __________.

Inhibitor

Tamoxifen is a P-Glycoprotein __________.

Inhibitor

Digoxin is a P-Glycoprotein __________.

Substrate

Give the P-Glycoprotien and P450 status of verapamil.

p450

Inhibitor

Substrate

P-Glycoprotein

Inhibitor

Substrate

Give the P-Glycoprotien and P450 status of Tamoxifen.

P-Glycoprotien

Inhibitor

P450 Prodrug

Substrate

Inhibitor

Give the P-Glycoprotien and P450 status of Midazolam.

P-Glycoprotien Inhibitor

P450 Substrate

This is the is concerned with the processes that determine the concentration of drugs in body fluids and tissues over time, including drug absorption, distribution, biotransformation (metabolism), and excretion.

Pharmacokinetics

If you're concerned about what a drug is doing at a certain organ, are you concerned with pharmacokinetics or pharmacodynamics?

Pharmacodynamics

This is the study of the actions of drugs on target organs.

Pharmacodynamics

If you're concerned about how a drug is absorbed, are you concerned with pharmacokinetics or pharmacodynamics?

Pharmacokinetics

Name a Class III cardiac drug that will increase Digoxin levels.

Amiodarone

If you're concerned about what the body does to the drug, are you concerned about pharmacodynamics or pharmacokinetics?

Pharmacokinetics

Note: Pharmacokinetics is what the body does to the drug, pharmacodynamics is what the drug does to the body.

This is a chemical that inhibits the use of a metabolite in a biochemical pathway; e.g., methotrexate inhibits dihydrofolate reductase (DHFR) and thus prevents folate from being recycled.

Antimetabolite

Note: Therefore, methotrexate (just like Bactrim in bacteria) is an antimetabolite in humans and is thus used as an immunosupressant medication.

This is the study of poisons that focuses on the harmful effects of drugs and other chemicals and on the mechanisms by which these agents produce pathologic changes, disease, and death.

Toxicology

While drugs may actually be hormones or neurotransmitters that are produced inside the body, this type of drug can also be produced from outside the body either by synthetic or natural means.

Xenobiotic

A ______ is a drug that can kill, whereas a ______ is a drug that can kill and is produced by a living organism.

Poison, Toxin

Note: Toxins are produced by a living organism. Think of this in terms of TSS... Toxins are produced by living bacteria.

Give the equation for Clearance

C = Elimination Rate (mg/hr)/Drug Concentration (mg/L)

Clearance = L/Hr

This is the process by which drugs are changed in the body.

Biotransformation

This is the biomedical science concerned with the interaction of chemical substances with living cells, tissues, and organisms.

Pharmacology

The ________ of a drug is the fraction of an administered dose that is unchanged that reaches systemic circulation.

Bioavailability

Amiodarone

Class: ANTIARRYTHMIC AGENT, CLASS III

CP450 status: INHIBITOR/SUBSTRATE

P-glyco status: INHIBITOR/SUBSTRATE

amiodarone

Class 3 antiarrythmic

Amiodarone

Class: antiarrhythmic

Cytochrome P450 status: Substrate & Inhibitor

P-glycoprotein stats: Substrate & Inhibitor

Amiodarone

Class: antiarrhythmic

Cytochrome P450 status: Substrate & Inhibitor

P-glycoprotein stats: Inhibitor

Carbamazepine

Class: ANTICONVULSANT

CP450 status: INDUCER/SUBSTRATE

P-glyco status: INDUCER

Carbamazepine

anticonvulsant

Carbamazepine

Class: Anticonvulsant, anti-epileptic agent

Cytochrome P450 status: Substrate & Inducer

P-glycoprotein status: Inducer

carbamazepine

Na+ channel blocker

CYP inducer

*oxcarbazepine less drug interaction

Henderson-Hassalbach

pKa = pH - log [A-] / [HA]

Note: When there's an equal amount of acid and base, you get log of 1... this is zero. Therefore pka then equals pH.

Cimetidine

Class: HISTAMINE H2 ANTAGONIST

CP450 status: INHIBITOR

P-glyco status: SUBSTRATE

Cimetidine

H2 Antagonist

Cimetidine

Class: Histamine H2 receptor antagonist

Cytochrome P450 status: Inhibitor

P-glycoprotein status: Substrate

Which is absorbed more readily in the stomach, weak acids or weak basis?

Weak acids

Note: Weak bases are more frequently ionized in the stomach because of the low pH (have a more positive charge). Thus weak acids are absorbed better.

Note: Greater surface area of stomach does outweigh this ionization effect with regards to weak acids and their absorption.

Clopidogrel

Class: ANTIPLATELET

CP450 Status: SUBSTRATE/INHIBITOR

Clopidogrel is a ....

Thienopyridine

Clopidogrel

Anti-platelet

Clopidogrel

Class: Platelet inhibitor, Decreased platelet aggregation

Cytochrome P450 status: Substrate & Inhibitor

P-glycoprotein status: N/A

While acidic drugs primarily bind to albumin, basic drugs bind to...

Glycoproteins

Beta-Globulins

This enzyme metabolizes caffeine and the bronchodilator theophylline.

Xanthine Oxidase

This is the amount of time it takes for 1/2 of the drug to be cleared.

The study of the structural, biochemical, and functional changes in cells, tissues, and organs that underlie disease to explain the whys and wherefores of the signs and symptoms manifested by patients while providing a rational basis for clinical care and therapy.

- Bridges basic science and clinical medicine

- The scientific foundation of all medicine

- General Pathology v. Systemic Pathology

Pathology

The study of the structural, biochemical, and functional changes in cells, tissues, and organs that underlie disease.

pathology

the study of disease

a significant component of the causal study of disease and a major field in modern medical practice and diagnosis

White infarct, ischemic necrosis.

Etiology

The cause of a disease. A majority of diseases do not have one etiologic agent though, often they are multifactorial.

The biochemical and molecular mechanisms of disease development. The sequence of cellular, biochemical, and molecular events that follow the exposure of cells or tissues to an injurious agent. It's the steps in between the cause and the effect.

Pathogenesis

The sequence of cellular, biochemical, and molecular events that follow the exposure of cells or tissues to an injurious agent.

pathogenesis

mechanism of development of disease; sequence of events in the response of cells or tissues to the etiological agent from initial stimulus to expression of disease

Morphologic Changes

The structural alterations induced in the cells and organs of the body that are either characteristic of a disease or diagnostic of an etiologic process - a cornerstone of diagnosis. Morphology has been used to determine the nature of a disease and it's progression, but it can be tough, like indistinguishable morphology amongst tumors.

Morphologic Changes

the structural alterations induced in the cells and organs of the body that are either characteristic of a disease or diagnostic of an etiologic process

morphologic changes

structural changes in cells or tissues that are either characteristic of disease or diagnostic of an etiologic process

Hyperplasia

An adaptation to a stimulus via an INCREASE IN CELL NUMBER, resulting from growth factor driven proliferation of mature cells, and in some cases, by increased output of new cells from tissue stem cells (occurs in cells capable of cell division).

- Can be physiologic or pathologic --> usually in response to hormones and other GF.

- often occurs with hypertrophy

Hyperplasia

Increase in the number of cells in an organ or tissue in response to a stimulus

hyperplasia

abnormal increase in number of cells in an organ or tissue; usually results in increased mass of the organ/tissue

Hypertrophy

An adaptation via an INCREASE IN THE CELL SIZE, resulting in increase in organ size. Not new cells, just bigger cells (often in cells that can't divide); Usually in response to increased workload. Due to the synthesis and assembly of additional intracellular structural components (proteins) induced by growth factors produced in response to mechanical stress or other stimuli.

Hypertrophy

Increase in cell size, resulting in an increase in the size of the affected organ. Often in cells that cant divide in response to increased workload.

hypertrophy

abnormal increase in size of cells resulting in an increase in organ size

Hypoplasia

An adaptation via an DECREASE IN CELL NUMBER.

Hypoplasia

decrease in cell number

hypoplasia

incomplete development or decreased size or an organ with a decreased number of cells

Atrophy

Decreased cell and organ size, as a result of decreased nutrient supply or disuse; associated with decreased synthesis of cellular building blocks and increased breakdown of cellular organelles

- Physiologic atrophy is common during normal development.

- Pathologic atrophy has man causes and can be local or generalized: decreased workload, loss of innervation, diminished blood supply, inadequate nutrition, loss or endocrine stimulation, or pressure.

Atrophy

A reduction in the size of an organ or tissue due to decrease in cell size and number because of decreased nutrient supply or disuse

atrophy

reduced size in an organ or tissue from a decrease in cell size

Adaptation

A functional and structural response, such as a reversible change in size, number, phenotype metabolic activity or cell function, to change in the physiologic state or pathologic stimuli response.

Adaptation

Reversible functional and structural responses to changes in physiologic states and some pathologic stimuli, during which new and altered stead states are achieved, allowing the cell to survive and continue to function.

Metaplasia

Change in phenotype of differentiated cells, often in response to chronic irritation (like smoking columnar to squamous in RT) that makes cells better able to withstand the stress; usually induced by altered differentiation pathway of tissue stem cells; may result in reduced functions or increased propensity for malignant transformation

Metaplasia

A reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type

metaplasia

reversible change in which one differentiated cell type is replaced by another cell type; normal to normal (but not in right place)

Differentiation

The develop of a cell from a stem cell or undifferentiated mesenchymal cell into a specific cell pathway/type. Differentiation is directed by signals generated by cytokines, GF's,and ECM components in the cell's environment, that promote the expression of genes to push the cell down a pathway. Metaplasia can reprogram this pathway.

differentiation

a less specialized cell type turns into a more specialized cell type

Necrosis

Accidental and unregulated cell death from damage to cell membranes and loss of ion homeostasis, so severe that lysosomal enzymes enter the cytoplasm and digest the cell as it's components often leak out. Results from many common injuries such as ischemia, toxin exposure, various infections, and trauma. It is always a pathologic process.

Accidental and unregulated cell death from damage to cell membranes and loss of ion homeostasis. The result of denaturation of intracellular proteins and enzymatic digestion of the lethally injured cell. Eosinophilia, nuclear shrinkage.

necrosis

inflammatory cell death characterized by denaturation of intracellular proteins and enzymatic digestion of a lethally injured cell

Ischemia

the most common type of cell injury in clinical medicine and it results from hypoxia induced by reduced blood flow, most commonly due to a mechanical arterial obstruction. Ischemia compromises the delivery of substrates for glycolysis, causing more rapid and severe cell/tissue injury. Ischemia is reversible if oxygen is restored, however, if it persists, irreversible injury and necrosis ensue.

A high conductance channel in the mitochondrial membrane that results from damage. It's opening leads to loss of membrane potential, causing a failure in oxidative phosphorylation and progressive depletion of ATP --> necrosis. Protein cyclophilin D is a structural component that is often targeted to immunosuppressive drug cylcosporine which acts to reduce the pore opening size.

Reactive Oxygen Species

ROS are a type of oxygen-derived free radical that are normally produced during mitochondrial respiration & energy generation, but are degraded and removed by cellular defense systems. ROS are also made by activated leukocytes, like neutrophils and macrophages during inflammation, to destroy microbes and dead particles. Too many ROS leads to oxidative stress, implicated in many pathogenic processes, such as lipid peroxidation, oxidative modification of proteins, or lesions in DNA.

Reactive Oxygen Species

type of oxygen-deprived free radical that is normally produced during mitochondrial respiration and energy generation, but is degraded and removed by cellular defense systems.

reactive oxygen species

chemically-reactive molecules containing oxygen, formed as a natural bi-product of oxygen metabolism; involved in cell signaling, can cause damage if scavenging mechanisms not in place

Ischemia-Reperfusion Injury

Restoration of blood flow to ischemic tissues can promote recovery of cells if they are reversibly injured, but it can also exacerbate the injury and cause cell death, leading to tissue damage.

- Some mechanisms include oxidative stress from ROS/NOS species, intracellular calcium overload from Ca influx-->mitochondrial damage, inflammation, and activation of a complement system where IgM ab deposit in ischemic tissues and are later activated to cause damage.

Ischemia-Reperfusion injury

Restoration of blood flow to ischemic tissues can promote recovery of cells if they are reversibly injured, but can also exacerbate the injury and cause cell death, leading to tissue damage.

ischemia/reperfusion injury

when bloodflow is restored to a site that was recently blood-deficient; nutrients in blood cause oxidative stress and inflammation

Mitochondrial / Intrinsic Pathway of Apoptosis

Pathway triggered by loss of survival signals, DNA damage, and accumulation of mis-folded proteins (ER stress); associated with leakage of pro-apoptotic proteins from mitochondrial membrane into the cytoplasm, where they activate caspases. This path is inhibited by anti-apoptotic members of the BCL2 family, which are induced by survival signals, including GFs.

Mitochondrial/Intrinsic pathway of apoptosis

major mechanism, triggered by loss of survival signals, DNA damage, and accumulation of misfolded proteins (ER stress). Associated with leakage of pro-apoptotic proteins form mitochondrial membrane into the cytoplasm, where they activate caspases

intrinsic (mitochondrial) pathway of apoptosis

due to increased permeability in mitochondrial membrane, leakage of pro-apoptotic molecules into the cytoplasm

Apoptosis

Regulated mechanism of cell death that serves to eliminate unwanted and irreparably damaged cells, with the least possible host reaction. Characterized by enzymatic degradation of proteins and DNA, initiated by caspases; and by recognition and removal of dead cells by phagocytes.

Two major pathways:

- Mitochondrial/Intrinsic Pathway

- Death Receptor/Extrinsic Pathway

Apoptosis

Regulated mechanism of cell death that serves to eliminate unwanted and irreparably damaged cells, with the least possible host reaction

Responsible for elimination of self-reactive lymphocytes and damage by cytotoxic T lymphocytes; is initiated by engagement of death receptors (members of TNF receptor family) by ligands on adjacent cells.

Necroptosis

"Programmed necrosis" or "caspase-independent programmed cell death". It is triggered by genetically programmed signal transduction events (apoptosis-like) leading to cell death from loss of ATP, swelling of cell and organelles, generation of ROS, release of lysosomal enzymes, and ultimately plasma membrane rupture (necrosis-like). It is triggered by ligation of TNFR1, and viral proteins of RNA and DNA viruses. It is caspase-independent but is dependent on signalling by RIP1 and RIP3 complexes.

the abnormal tissue deposition of calcium salts, together with small amounts of Fe, Mg, and other mineral salts.

- Two Types: Dystrophic v. Metastatic

Pathologic calcification

the abnormal tissue deposition of calcium salts, together with small amounts of Fe, Mg, and other mineral salts

Dystrophic Calcification

Path calcification in areas of necrosis. Can tell of previous cell injury or can cause organ dysfunction (atherosclerosis and calcific valvular disease). Serum Ca is normal in dystrophic calcification.

Dystrophic calcification

Pathologic calcification in areas of necrosis. Can tell of previous cell injury or a cause of organ dysfunction.

dystrophic calcification

local deposition of calcium in dying tissues; occurs despite normal serum levels of calcium and in absence of derangements of calcium metabolism

Metastatic Calcification

May occur in normal tissues whenever there is hypercalcemia (usually from PTH excess). Can occur all over the body but usually gastric mucosa, kidneys, lungs, system arteries, and pulmonary veins because these tissues excrete acid and hence have an internal alkaline compartment.

Metastatic calcification

Pathologic calcification that may occur in normal tissues whenever there is hypercalcemia.

metastatic calcification

deposition of calcium salts in otherwise normal tissues; ALMOST ALWAYS a result of hypercalcemia secondary to some disturbance in calcium metabolism

Telomere

Short repeated sequences of DNA present at the ends of linear chromosomes that important for ensuring the complete replication of chromosome ends and for protecting the ends from fusion and degradation. Telomeres progressively get shorter because telomerase, which adds nucleotides to telomeres, is only expressed in germ cells and low levels in stem cells.

Telomere

Short repeated sequences of DNA present at the ends of linear chromosomes that are important for ensuring the complete replication of chromosome ends and for protecting the ends from fusion and degradation.

telomere

short, repeated sequences of DNA (TTAGGG) present at the linear ends of chromosomes that are important for ensuring complete replication of chromosomal ends and for protecting chromosomal termini from fusion and degradation. When each cell replicates a

small section of the this is not replicated

Sirtuins

A family of NAD-dependent protein deacetylases; 7 types in different cellular compartments and have non-redundant functions designed to adapt bodily functions to various environmental stresses like food deprivation and DNA damage. Sirtuins' products increase longevity such as proteins that inhibit metabolic activity, inhibit apoptosis, stimulate protein folding, and inhibit oxygen radicals, as well as increase insulin sensitivity and glucose metabolism.

Sirtuins

A family of NAD-dependent protein deacetylases, designed to adapt bodily functions to various environmental stresses like food deprivation and DNA damage.

sirtuins

A class of proteins that possess either mono-ADP-ribosyltransferase, or deacylase activityregulate; important biological pathways in bacteria, archaea and eukaryotes

They have been implicated in influencing a wide range of cellular processes like aging, transcription, apoptosis, inflammation and stress resistance, as well as energy efficiency and alertness during low-calorie situations

Adrenergic Neurotransmission

A nerve ending that releases norepinephrine as the primary transmitter

located on most types of smooth muscle, cardiac muscle, some presynaptic terminals, and lipocytes.

beta adrenoreceptor

receptors with subtypes β1, β2, and β3. Usually activate Gs

Bioequivalent

When a generic drug is made that has the same content, purity, and bioavailability as the original product

bioequivalence

used to assess the in vivo biological equivalence of two proprietary preparations of a drug

these type of drugs are for all intents and purposes the same

"black box" warning

the strongest warning that the FDA requires, and signifies that medical studies indicate that the drug carries a significant risk of serious or even life-threatening adverse effects

black box warning

strongest warning possible from the FDA that can be put on the insert label of a drug; signifies medical literature demonstrates serious or even fatal adverse events associated with the drug

Competitive antagonist

A pharmacologic antagonist that can be overcome by increasing the concentration of agonist

Irreversible antagonist

A pharmacologic antagonist that cannot be overcome by increasing agonist concentration

Physiologic dependence

An altered state that leads to an abstinence syndrome (withdrawal state) when the drug is discontinued.

Psychological dependence

Manifested by the compulsive use of drugs to reduce anxiety.

psychological dependence

deals with release of dopmaine (reward NT) in synapses of the nucleus accumbens

active during the stimulation of the brain reward pathway and dopamine is necessary for this

Downregulation of receptors

Long-term reductions in receptor number in response to continuous exposure to agonists.

Drug clearance

The ratio of the rate of elimination of a drug to the concentration of the drug in the plasma or blood

drug clearance

parameter that limits the time course of drug action at the target organ

(metabolism + excretion)/(drug concentration in plasma)

Pharmacokinetics

The actions of the body on the drug, including absorption, distribution, metabolism, and elimination.

pharmacokinetics

the fate of a drug from the moment that it is administered up to the point at which it is completely eliminated from the body. This principle describes how the body affects a specific drug after administration through the mechanisms of absorption and distribution, as well as the chemical changes of the substance in the body (e.g. by metabolic enzymes such as cytochrome P450 orglucuronosyltransferase enzymes), and the effects and routes of excretion of the metabolites of the drug.

Pharmacodynamics

The actions of a drug on the body, including receptor interactions, dose-response phenomena, and mechanisms of therapeutic and toxic actions

pharmacodynamics

study of drug-receptor interactions, relationship between drug concentration and effect.

Enteral drug administration

routes in which the drug is absorbed from the gastrointestinal tract

enteral drug administration

administered by mouth, must survive GI system, be able to be absorbed, and survive first pass metabolism in the liver

Parenteral drug administration

drug administration with a needle and syringe or with an intravenous infusion pump

A response of vascularized tissues to infections and damaged tissues that brings cells and molecules of host defense from the circulation to the sites where they are needed, in order to eliminiate the offending agents

inflammation

complex reaction in tissues that mainly involves blood vessels and leukocytes; can be acute or chronic

5 R's of Inflammatory Response

1. Recognition of the injurious agent

2. Recruitment of Leukocytes

3. Removal of the agent

4. Regulation (control) of the response

5. Resolution/Repair

5 R's of Inflammatory Response

1. Recognition of the injurious agent

2. Recruitment of leukocytes

3. Removal of agent

4. Regulation of the response

5. Resolution/Repair

Inflammasome

All cells have cytosolic receptors that recognize a diverse set of molecules related to cell damage. These receptors activate a multi-protein cytosolic complex called the INFLAMMASOME, which induces the production of IL-1 --> IL-1 recruits leukocytes and thus induces inflammation.

a component of the innate immune system expressed in myeloid cells, it is a multiprotein oligomer consisting of caspase 1, PYCARD, NALP and sometimes caspase 5

responsible for activation of inflammatory processes, and has been shown to induce cell pyroptosis, a process of programmed cell death distinct from apoptosis

Acute Inflammation

the initial rapid response to infections and tissue damage that develops in min-hrs and lasts only hrs-days. the 3 major components are: 1) dilation of small vessels to increase blood flow, 2) increased permeability of microvasculature enabling plasma proteins and leukocytes to eave the circulation and 3) emigration of leukocytes from microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent.

Acute Inflammation

The initial rapid response to infections and tissue damage that develops min-hrs and lasts only hrs-days.

acute inflammation

rapid onset (minutes) and of short duration (few hours or days); exudation of fluid and plasma proteins (edema) and migration of leukocytes

First pass effect

The elimination of a drug that occurs after administration but before it enters the systemic circulation (eg, during passage through the gut wall, portal circulation, or liver for an orally administered drug).

first pass effect

liver has first shot at metabolizing orally administered drugs. must take this into account when dosing

Glucocorticoid

Steroid hormones produced by the adrenal cortex, have important effects on intermediary metabolism, catabolism, immune responses, and inflammation (eg, cortisol).

glucocorticoid

metabolization of glucose, produced in adrenal cortex, steroid hormone

Steroid hormones produced by the adrenal cortex which regulate sodium and potassium reabsorption in the collecting tubules of the kidney (eg, aldosterone).

mineralocorticoid

steroid hormone influencing salt and water balances in the body.

ALDOSTERONE

Loading dose

The dose required to achieve a specific plasma drug concentration level with a single administration

loading dose

dosage that circumvents lowering of drug plasma concentration by providing a sufficient amount of drug to obtain an appropriate serum concentration after only one or two doses

Maintenance dose

The dose required for regular administration to maintain a target plasma level

maintenance dose

dose given once steady state equilibrium between plasma concentration and tissue concentration is acheived

subsequent doses need only to replace amount of drug that was lost through metabolism and excretion

Neutrophil Extracellular Traps (NETs)

extracellular fibrillar networks that provide a high concentration of antimicrobial substances at sites of infection and prevent the spread of the microbes by trapping them in the fibrils. Made in response to infectious pathogens (bacteria, fungi), inflammatory mediators (chemokines, cytokines, complement proteins and ROS).

Neutrophil Extracellular Traps (NETs)

Extracellular fibrillar networks that provide a high concentration of antimicrobial substances at sites of infection and prevent the spread of the microbes by trapping them in their fibrils

Complement System

Reacts against microbes and produces mediators of inflammation. Results in C3a/C5a for Inflammation, C3b for phagocytosis, and MAC for microbe lysis

- Alternative, Classical, and Lectin Pathways

Complement System

Reacts against microbes and produces mediators of inflammation

complement system

helps the ability of antibodies and phagocytic cells to clear pathogens from an organism

When stimulated by one of several triggers, proteases in the system cleave specific proteins to release cytokines and initiate an amplifying cascade of further cleavages. The end-result of this activation cascade is massive amplification of the response and activation of the cell-killing membrane attack complex

Transmigration / Diapedesis

The second step of leukocyte recruitment when leukocytes pass through the endothelium of postcapillary venules. Chemokines act on the adherent leukocytes and stimulate cells to migrate through endothelial spaces towards the injury or infection. Adhesion molecules like CD31 and PECAM-1 help. After they cross, they pierce the basement membrane and enter the extravascular tissue. .

Transmigration/Diapedesis

When leukocytes pass through the endothelium of postcapillary venules towards the injury or infection. After they cross, they pierce the basement membrane and enter the extravascular tissue

transmigration (diapedesis)

leukocyte migration through the endothelium

P-glycoprotein inducers

Increases elimination of drugs from the cytoplasm of epithelial and cancer cells into the extracellular space (ie, from the intestinal mucosa into the lumen)

P-glycoprotein inhibitors

Mimic drug metabolism inhibitors by increasing bioavailability

Chemotaxis

Last step of leukocyte recruitment, where leukocytes exit circulation and move in tissues toward the site of injury, AKA locomotion along a chemical gradient. Chemotactic agents bind to specific TM G Protein coupled receptors on leukocytes, signal to activate secondary messengers to induced actin polymerization within the filopodia to roll the leukocyte toward the inflammatory stimulus in the direction of the locally produced chemoattractants.

Chemotaxis

Where leukocytes exit circulation and move in tissues towards the site of injury, AKA locomotion along a chemical gradient

chemotaxis

locomotion along a chemical gradient

Transcytosis

Increased transport of fluids and proteins through the endothelial cell and help increase vascular permeability in response to stimuli during inflammation

transcytosis

process by which various macromolecules are transported across the interior of a cell

Pharmacodynamic interaction

A change in the pharmacodynamics of 1 drugs caused by the interacting drug (additive action of 2 drugs having similar effects)

Pharmacokinetic interaction

A change in the pharmacokinetics of 1 drug caused by the interacting drug (eg, an inducer of hepatic enzymes)

Phagocytosis

Three steps of 1) recognition and attachment of the particle to be ingested by the leukocyte, 2) engulfment, with subsequent formation of a phagocytic vacuole, and 3) killing or degradation of the ingested material.

Inflammation marked by the exudation of cell-poor fluid into spaces created by cell injury (like a skin blister) or into the body cavities, resulting in an effusion.

Fibrinous Inflammation

Inflammation marked by a fibrinous exudate develops when the vascular leaks are large or there is a local procoagulant stimulus (i.e. cancer cells). It's characteristic of inflammation in the lining of body cavities, such as the meninges, pericardium, and pleura.

Fibrinous Inflammation

Inflammation marked by a blood-clot exudate. Develops when the vascular leaks are large or there is a local procoagulant stimulus. Characteristic of inflammation in lining of body cavities, such as meninges, pericardium, pleura

fibrinous inflammation

a large increase in vascular permeability allows fibrin to pass through the blood vessels. If an appropriate procoagulativestimulus is present, such as cancer cells, a fibrinous exudate is deposited

Pharmacodynamic tolerance

adaptations to chronic drug exposure at the tissue and receptor level

pharmacodynamic tolerance

results from changes in the drug-receptor interactions

MOST IMPORTANT

What is pharmacodynamic tolerance?

when the same concentration of a drug at a receptor produces less of an effect than it normally would

Pharmacokinetic tolerance

caused by accelerated drug elimination, usually resulting from an up-regulation of the enzymes that metabolize the drug

pharmacokinetic tolerance

develops when ability to metabolize or excrete the drug increases over time

What is pharmacokinetic tolerance?

increased drug metabolism leads to decreased concentration and effect

Purulent (Suppurative) Inflammation

Inflammation marked by the production of pus, an exudate consisting of neutrophils, the liquefied debris of necrotic cells, and edema fluid, most frequently caused by infection with bacteria that cause liquefactive tissue necrosis - pyogenic (pus-producing) bacteria. Abscesses are localized collections of purulent inflammatory tissue cause by suppuration buried in a tissue, an organ, or a confined space.

Purulent (Suppurative) Inflammation

Inflammation marked by the production of pus, an exudate consisting of neutrophils, the liquefied debris of necrotic cells, and edema fluid

Chronic Inflammation

A prolonged host response to persistent stimuli caused by microbes that resist elimination, immune responses against self & environmental antigens, and some toxic substances. It is characterized by coexisting inflammation, tissue injury, attempted repair by scarring, and immune response. The cellular infiltrate consists of macrophages, lymphocytes, plasma cells, and other leukocytes, and these make cytokines that mediate the process.

long duration; associated with the presence of lymphocytes and macrophages, the proliferation of blood vessels, fibrosis, and tissue destruction.

Granuloma

a pattern of chronic inflammation induced by T cell and macrophage activation in response to an agent that is resistant to eradication. The activated macrophages may develop abundant cytoplasm and begin to resemble epithelial cells - Epitheloid Cells. Some activated macrophages may fuse to form multinucleate Giant Cells.

- Foreign body granulomas v. Immune granulomas.

Granuloma

Cellular attempt to contain an offending agent. Pattern of chronic inflammation induced by T cell and macrophage activation in response to an agent that is resistant to eradication

granuloma

focus of chronic inflammation consisting of a microscopic aggregation of macrophages that are transformed into epithelium like cells surrounded by a collar of mononuclear leukocytes principally lymphocytes and occasionally plasma cells

Acute Phase Proteins

Plasma proteins, mostly made in the liver, whose plasma concentrations increase several 100-fold in response to inflammatory stimuli. Synthesis is stimulated by cytokines like IL-6 (for CRP & fibrinogen) and IL-1 or TNF (for SAA)

Plasma proteins, mostly made in the liver, whose plasma concentration increase several hundred fold in response to inflammatory stimuli

acute phase proteins

plasma proteins, mostly synthesized in the liver, whose plasma concentrations may increase several hundred fold as part of the response to inflammatory stimuli [IL-6, TNF, IL-1]

***3 most common are C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen****

Leukocytosis:

cytokines (colony-stimulating factors) stimulate production of leukocytes from precursors in the bone marrow (induced by things like prolonged infection), in order to compensate for the loss of leukocytes in the inflammatory reaction; is associated with a rise in the number of more immature neutrophils in the blood ('left shift').

Leukocytosis

Cytokines stimulate production of leukocytes from precursors in the bone marrow in order to compensate for the loss of leukocytes in the inflammatory reaction

leukocytosis

an increase in the number of white cells in the blood

(a common reaction to a variety of inflammatory states)

Repair

Or 'healing', is restoration of tissue architecture and function after an injury, occurring by two types of reactions: regeneration by proliferation of residual (uninjured) cells & maturation of tissue stem cells, and the deposition of connective tissue to form a scar.

Repair

"healing", restoration of tissue architecture and function after an injury

repair

may restore some original structures but can cause structural derangements (normal structure altered); often consists of a combo of regeneration & scar formation by the deposition of collagen

Regeneration

Some tissues can replace the damaged components and essentially return to a normal state as proliferation of cells that survive the injury rapidly divide, like in the epithelia of the skin, the intestines, or the liver.

Regeneration

Replace damaged components and return to a normal state as proliferation of cells that survive the injury rapidly divide

regeneration

proliferation of cells & tissues to replace lost or damaged cells and tissues; normal structure is restored

Connective Tissue Deposition

Scar formation happens when the injured tissues can't restitute themselves or if the supporting structures of the tissue are severely damaged, connective (fibrous) tissue is laid down to provide enough structural stability that the injured tissue can function. Fibrosis is too much collagen in an organ after chronic inflammation.

Angiogenesis:

This is the first step in scar formation. the formation of new blood vessels from existing ones, which supply nutrients and oxygen needed to support the repair process, but they are leaky as a result of incomplete inter-endothelial junctions & VEGF increasing vascular permeability, causing some edema.

Formation of new blood vessels from existing ones, which supply nutrients and oxygen needed to support the repair process. Leaky, so cause some edema.

angiogenesis

physiological process through which new blood vessels form from pre-existing vessels

Granulation Tissue

The 2nd step of scar formation. Formed by the migration and proliferation of fibroblasts and deposition of loos connective tissue, together with the vessels and interspersed leukocytes. It progressively invade the injury site. This is the soft pink tissue under a scab. Transforming GF-beta is the most important cytokine for this process.

Granulation tissue

migration and proliferation of fibroblasts and deposition of loose connective tissue, together with the vessels and interspersed leukocytes

granulation tissue

a special type of tissue formed in the first 24-72 hours of the tissue repair process by fibroblast and vascular endothelial cell proliferation. It has a pink, soft, granular appearance on the wound surface and is the hallmark of tissue repair

Remodeling of Connective Tissue

3rd step of scar formation. The maturation and reorganization of the connective tissue (remodeling) produce the stable fibrous scar. This depends on a balance between fibrogenic agents, metaloproteinases (MMPs) that digest ECM, and the tissue inhibitors of MMPs (TIMPs).

Remodeling of connective tissue

the maturation and reorganization of the connective tissue to produce the stable fibrous scar

remodeling of connective tissue

The reorganization or renovation of existing tissues. This process can either change the characteristics of a tissue such as in blood vessel remodeling, or result in the dynamic equilibrium of a tissue such as in bone remodeling

Healing by 1st Intention

AKA epithelial regeneration, The principal mechanism of repair when the injury involves only the epithelial layer, such as the healing of a clean, uninfected surgical incision.

- 3 processes: inflammation, proliferation of epithelial and other cells, and maturation of the CT scar.

- Primary Union

Healing by 1st Intention

AKA epithelial regeneration, the principal mechanism of repair when the injury involves only the epithelial layer

Healing by 2nd Intention

The repair process involving a combo of regeneration and scarring when cell or tissue loss is more extensive, like large wounds, abscesses, ulceration, and ischemic necrosis (Infarction) in parenchymal organs. Everything is larger (fibrin clot, inflammation, granulation tissue, etc.)

- Secondary Union

Healing by 2nd Intention

The repair process involving a combination of regeneration and scarring when cell or tissue loss is more extensive, like large wounds, abscesses, ulceration, and ischemic necrosis in parenchymal organs

Fibrosis

The excessive deposition of collagen and other ECM components in a tissue, usually in internal organs in chronic diseases, induced by persistent injurious stimuli and typically associated with loss of tissue. May cause organ dysfunction or failure.

- TGF-beta is the major cytokine.

Fibrosis

The excessive deposition of collagen and other ECM components in a tissue

fibrosis

excessive deposition of collagen and other ECM components in a tissue; indicates chronic diseases

Hypertrophic Scar

the accumulation of excess amounts of collagen can cause a raised scar, generally developing after thermal or traumatic injury that involves deep layers of the dermis

Hypertrophic scar

the accumulation of excess amounts of collagen that can cause a raised scar

hypertrophic scar

a cutaneous condition characterized by deposits of excessive amounts of collagen which gives rise to a raised scar

NOTE

-they do not extend beyond the boundary of the original wound, but may continue to thicken for up to six months.

Keloid

accumulation of excessive amounts of collagen to a point where the scar tissue grows beyond the boundaries of the original wound and does not digress. Keloid formation is a individual predisposition, and is more common in African Americans.

Keloid

Accumulation of excessive amounts of collagen to a point where the scar tissue grows beyond the boundaries of the original wound and does not digress

keloid

a raised (hypertrophic) scar that grows beyond the boundaries of the original wound and does not regress; forms due to excess collagen deposition in the skin

This will bind to a receptor and cause the opposite reaction that is caused by the agonist. It will decrease the receptor to below its baseline function.

Inverse Agonist

An example of this would be the receptor that T cells use which has IL-2 (which is secreted by activated T cells) as its ligand.

Autoreceptor

This is the amount of drug that is available to the tissue that is being targeted.

Bioavailability

If two drugs are termer _______, they are, for all intensive purposes in pharmacology, the same.

Bioequivalant

This is a type of warning that appears on the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administration specifies that it is formatted with a 'box' or border around the text

Black Box Warning

Note: It is the strongest warning that the FDA requires, and signifies that medical studies indicate that the drug carries a significant risk of serious or even life-threatening adverse effects.

Tyrosine is the precursor for 3 amine neurotransmitters that contain catechol group. What are they?

1. Dopamine

2. Norepinephrine

3. Epinephrine

These contain a catechol group and an amine group. They are often neurotransmitters.

Catecholamines

What are the two enzymes that break down catecholamines and Serotonin (another bioenergetic amine)?

Monoamine oxidase (MAO)

Catechol-O-Methyl Transferase (COMT)

This is something that combines permanently with the active site of the receptor and doesn't allow for the agonist binding (and is insurmountable).

Noncompetitive (Irreversible) Active Site Antagonist

These are paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

FDA Medication Guides

This is a class of steroid hormones that is characterized by its influence on water/salt balance.

Mineralcorticoids

This term refers to both glucocorticoids and mineralcorticoids.

Corticosteroids

This is a dose-response curve based off of drug concentration alone.

Graded Dose-response Curve

This is a dose-response curve that is based off of the average effect of the drug.

Quantal dose-response curve

Long Non-coding RNA (lncRNA)

Noncoding region >200 nucleotides that modulate gene expression.

Ex: bind to regions of chromatin, restricting RNA polymerase access to coding genes within the region

This is an initial dose that is given to a patient that is higher than the subsequent doses for the purpose of achieving therapeutic drug concentrations in the serum very rapidly.

Loading Dose

This dose is given to maintain steady-state plasma concentrations within the drug's therapeutic range.

Maintenance Dose

This is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, unapproved dosage, or unapproved form of administration.

Off-Label Use

This is the technology to analyze how genetically different folks respond to drugs differently.

Pharmacogenomics

This is the concentration of a drug that induces a specified clinical effect in 50% of the subjects to which the drug is administered.

Potency (EC50)

This is the same as Vmax. It is the degree to which a drug is able to induce its maximal effect.

Efficacy

Mitochondrial permeability transition pore

A high conductance channel in the mitochondrial membrane. Opening leads to loss of membrane potential, causing a failure in oxidative phosphorylation and progressive depletion of ATP --> necrosis.

mitochondrial permeability transition pore

high conductance channels in mitochondrial membrane; leads to loss of protons and thus loss of mitochondrial membrane potential, resulting in failure of oxidative phosphorylation and progressive loss of ATP-->necrosis

Death receptor/Extrinsic pathway of apoptosis

Responsible form elimination of self-reactive lymphocytes and damage by cytotoxic T lymphocytes.

This type of sympathomimetic binds to the receptors (alpha or beta) and causes a RxN.

Direct Sympathomimetic

This type of sympathomimetic will cause the release of the sympathetic neurotransmitter (NE), but it will not bind to the post-synaptic receptor.

Indirect Sympathomimetic

This type of drug is a medication which inhibits the postganglionic functioning of the sympathetic nervous system.

Sympatholytic (Sympathoplegic)

E.g., beta-blockers

This is another word for a sympatholytic.

Sympathoplegic

This is an agent or factor that leads to malformation of an embryo.

Teratogen

This occurs because of a decreased quantity of the substance reaching the site it affects. This may be caused by an increase in induction of the enzymes required for degradation of the drug e.g. CYP450 enzymes. This is most commonly seen with substances such as ethanol, barbiturates and opiates.

Pharmacokinetic Tolerance

This occurs when the response to the substance is decreased by cellular mechanisms. This may be caused by a down regulation of receptor numbers[2] (or up regulation in the case of a receptor antagonist).

Pharmacodynamic Tolerance

This is a foreign chemical substance found within an organism that is not normally naturally produced by or expected to be present within that organism.

Xenobiotic

These are variable sequences (thousands to millions of base pairs) that differ between two individuals. They are different than SNPs because they are regions of base pairs, and because they account for most of the phenotypic variation between individuals.

Copy Number Variation

This is a basic unit of DNA packing in eukaryotes. It consists of a segment of DNA wound around an 8-histone protein core.

Nucleosome

These are covalent modifications that act as epigenetic signatures; e.g., acetylation sometimes leads to gene regulation on DNA sequences.

Histone Marks

These are small, non-coding, single-stranded RNAs that are incorporated into silencing complexes and can mediate post-transcriptional silencing of genes.